Dose Of Amikacin Research Articles (Page 1)

Abstract Background and Aims Amikacin, a key aminoglycoside for treating severe pediatric infections, requires precise dosing to achieve therapeutic efficacy while minimizing nephrotoxic risks. Effective treatment depends on achieving high peak concentrations (20–80 mg/L) to ensure bacterial eradication and maintaining low trough levels (2.5–5 mg/L) to prevent toxicity. However, dosing guidelines differ across centers and countries, leading to variations in achieving these targets across pediatric populations. We present an in-silico study to compare Amikacin peak and trough levels based on different dosing guidelines. We selected guidelines from France, the United States, and the United Kingdom, representing a diverse range of dosing strategies, with many low- and middle-income countries adopting practices that fall within these ranges. Method An in-silico pharmacokinetic (PK) model, adapted from [1] and validated against clinical data from [2], was used to simulate Amikacin dosing. A virtual pediatric population (N = 1000), accounting for maturational changes in GFR, weight, and height, was generated to match the study population in [5] (median [range] age: 6 months [0.8–89], weight: 6.6 kg [2.8–22], eGFR: 116 mL/min/1.73 m² [48–290]), where eGFR was determined based on serum creatinine using the Schwartz formula. The body surface area was calculated using Mosteller's formula. Simulations in Python evaluated 24-hour dosing regimens over 7 days, following national guidelines from France [3] (dose: 30 mg/kg, peak levels >60 mg/L, and trough levels <2.5 mg/L), Stanford's Lucile Packard Children's Hospital (US) [4] (dose: 15–30 mg/kg, peak levels >20 mg/L, and trough levels <2.5 mg/L), and Sheffield Children's NHS Foundation Trust (UK) [5] (dose: 20 mg/kg, trough levels <5 mg/L). Amikacin dosing was not held when trough levels were not met in simulations. Results Amikacin peak and trough concentrations varied across dosing guidelines (Fig. 1). Median peak levels for 30 mg/kg (French guideline) ranged from 61 to 74 mg/L over the treatment days, while 15 mg/kg (UK and US) produced lower peaks of 24–29 mg/L. The 20 mg/kg dose resulted in intermediate peaks of 42–51 mg/L. Trough levels showed distinct patterns of compliance with the defined thresholds (Table 1). For the stricter <2.5 mg/L threshold, compliance decreased over the 7-day period: 99.5% to 56.6% for 15 mg/kg, 93.5% to 34.8% for 20 mg/kg, and 71.9% to 9.6% for 30 mg/kg. For the UK's less stringent <5 mg/L threshold, compliance remained higher, with 96.3% at Day 7 for 15 mg/kg, 85.6% for 20 mg/kg, and 56.6% for 30 mg/kg. By Day 7, median trough levels for 30 mg/kg exceeded 2.5 mg/L in 90.4% of the population, while 43.4% exceeded 5 mg/L. For 15 mg/kg, 43.4% of the population exceeded 2.5 mg/L, but only 3.7% exceeded 5 mg/L. Conclusion The differences in dosing guidelines result in varying treatment efficacy and nephrotoxic risks, with substantial fractions of the pediatric population not meeting trough targets across all guidelines. Moreover, without adapting the dosing during treatment, trough levels progressively increase. This highlights the need for an improved understanding of Amikacin's nephrotoxic effects in pediatric patients and the development of optimized and harmonized dosing strategies.

Abstract Background and Aims Aminoglycosides, such as Amikacin, are the cornerstone to treat severe infections in pediatric patients. Amikacin dosing requires achieving high peak concentrations to ensure efficacy against bacterial strains (up to > 60 mg/L depending on the strain) while maintaining trough levels < 2.5 mg/L to minimize nephrotoxic risks [1]. The minimum effective dose and frequency has been a debate due to the challenges of predicting ontogeny physiological changes. Current dosing schemes often miss peak and trough target levels in pediatric populations [1]. We present an age-stratified in-silico study to evaluate Amikacin dosing strategies in pediatric patients aged 2 to 24 months, focusing on optimizing peak and trough levels within a 24-hour dosing interval. Method An in-silico pharmacokinetic (PK) model based on [2] was validated against the clinical study results in [1]. Age-stratified virtual pediatric populations (2–24 months) were generated to account for maturational changes in GFR, weight, and height age-dependence based on growth charts and GFR data derived from (51)Cr-EDTA clearance measurements using a single blood sample method [3, 4]. Virtual populations were created for 2-, 6-, 12-, and 24-month-old cohorts (Table 1). The body surface area was computed using Mosteller's formula. Simulations in Python were conducted to evaluate Amikacin dosing strategies with 24-hour dosing intervals over 5 days of treatment. Results Using the standard maximal dosing scheme of 30 mg/kg once daily [1], the simulation shows that the fraction of patients with trough levels > 2.5 mg/L after 24 hours was 61.3%, 19.7%, 4.7% and 1.1% for the 2-, 6-, 12-, and 24-month age cohorts, respectively. Simulations using an optimized 24-hours dosing scheme, designed to maximize peak levels while maintaining trough levels below 2.5 mg/L, revealed a marked age-dependent difference in peak concentrations (Fig. 1). Median peak concentrations after initial administration were 42.5 mg/L, 48.9 mg/L, 50.9 mg/L, and 52.0 mg/L for the 2-, 6-, 12-, and 24-month age cohorts, respectively. A fraction of 6.2% of 2-month-olds and 18.8% of 24-month-olds reached peak levels >60 mg/L after the initial administration. Peak concentrations declined progressively across all age groups over the treatment days. The median peak concentration decreased by 56.4% for the 2-month-olds and 13.8% for the 24-month-olds by day 5 of treatment. Moreover, by day 5, none of the 2-month-olds and 11.4% of the 24-month-olds reached peak concentrations >60 mg/L. Conclusion Further dosage stratification of Amikacin by age is necessary in infants due to physiological kidney maturation and other developmental changes. High inter-patient variability emphasizes the need for therapeutic drug monitoring and dose adjustments during the treatment to optimize efficacy while minimizing the risk of nephrotoxicity.

Combination antibiotics consisting of beta-lactam and aminoglycoside are commonly utilized in the treatment of neonatal septicaemia. The aims of this study were to (i) develop an externally validated population pharmacokinetic (PK) model, (ii) evaluate the attainment of target peak and trough serum concentrations by the current hospital amikacin dosing protocol and side effects, and (iii) compare intravenous (IV) versus intramuscular (IM) route of amikacin administration, in terms of attaining peak and trough serum concentration targets. Retrospective chart review was carried out over a 5-year period. All neonates who received amikacin with therapeutic drug monitoring performed were included in this study. A one-compartment population PK model was built, and external validation was performed. A total of 181 neonates (534 serum concentrations) were included in the population PK modeling and external validation. There was no apparent systematic bias in the predictions of the model. The external validation performed in the current study found the model to be generally unbiased. Sixty-one percent of the peak and 99% of the trough levels were within the targeted therapeutic ranges of 15-25 and <5 mg/L, respectively. There was no statistical difference in the proportion of trough concentrations that were within therapeutic range for IV as compared to IM, while IM resulted in a higher proportion of trough concentrations within therapeutic range, as well as higher peak concentrations. The current population PK model and external validation study have proven that the PK model built in the current study can be used to conduct reliable population simulations. IM injection can be an alternative route of administration for amikacin in neonates.

Biofilm-associated diseases have become a challenging issue for the healthcare system due to the aggregation of bacteria within the biofilm, which exhibits increased resistance to broad-spectrum antibiotics at standard or elevated concentrations. Consequently, adopting Chitosan-stabilized selenium nanoparticles (CS-SeNPs) is an efficient way to regulate biofilm creation. Multiple analyses were applied to characterize CS-SeNPs, including ultraviolet-visible absorption, Fourier Transform Infrared Spectroscopy, Zeta potential analysis, Dynamic Light Scattering analysis, Field emission Scanning Electron Microscopy, and Energy Dispersive x-ray. The antibacterial and antibiofilm properties of CS-SeNPs, AK: Cs-SeNPs, and amikacin (AK) were tested using 96-microtiter plates. The resulting data have revealed that CS-SeNPs at a wavelength of 244 nm were stabilized and rounded in shape with an average size of 68±23nm. The minimum inhibitory doses of AK and CS-SeNPs required to prevent the growth of P. mirabilis were 1000±398 and 50±0 µg/mL, respectively. The combination of AK:CS-SeNPs inhibited P. mirabilis strains at MIC of 160±0:12.5±0 µg/mL, which is lower than the MIC of AK and CS-SeNPs applied alone. The lowest concentrations of AK:CS-SeNPs, ranging between 66±23:5±1 μg /mL and 93±23:8±3 μg /Ml, successfully impeded the initial creation of P.mirabilis biofilm .The results demonstrate that The conjugation of AK:CS-SeNPs improves the amikacin's bactericidal efficiency, significantly hinders biofilm's initial development and reduces the viability of established biofilm created by multidrug-resistant P.mirabilis. This therapeutic approach has the potential to serve as a promising strategy for addressing Biofilm-associated diseases caused by resistant strains of P.mirabilis, conferring confidence in the battle against persistent infections.

Background: Aminoglycosides are potent bactericidal antibiotics primarily employed for gram-negative infections. However, they face limitations due to potential renal toxicity when administered at high doses. This study aimed to assess the nephrotoxicity of amikacin (AMK) at two distinct dosage levels over seven days in critically ill patients, utilizing renal-specific biomarkers. Methods: Critically ill patients with sepsis, severe sepsis, or septic shock were randomly assigned to two treatment groups receiving AMK in combination with a broad-spectrum β-lactam antibiotic according to antibiogram results. Disease severity was assessed using the Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores. Renal function was monitored through serum creatinine (SCr) and kidney injury biomarkers (NGAL and IL-18) measurements. Results: Among the 40 patients completing the study, the two groups had no significant differences in APACHE II (P = 0.39) and SOFA scores (P = 0.30). Baseline plasma creatinine levels exhibited no significant within-group differences. While NGAL levels in group 1(high dose AMK) significantly increased on day 3, no significant differences were observed between the groups in all four measurements (P = 0.03). Urinary IL-18 levels within groups demonstrated a significant increase peaking on day 3, with no significant within-group differences over the 7-day follow-up. Conclusion: The findings suggest that higher doses of AMK may be administered with a similar effect of low-dose AMK on renal function, as assessed by the RIFLE criteria (Risk, Injury, Failure, Loss, and End-stage kidney disease), a classification system used to evaluate acute kidney injury (AKI) severity in critically ill patients with sepsis.

To evaluate plasma and synovial fluid amikacin concentrations following cephalic or saphenous IV regional limb perfusion (IVRLP) with a dosing protocol of 25 mg of amikacin/kg, divided into 16.7 mg/kg systemically and 8.3 mg/kg regionally. We hypothesized that plasma amikacin concentrations observed at 30 minutes after systemic administration would exceed a therapeutic target of 53 μg/mL and that synovial fluid concentrations would exceed a therapeutic target of 80 μg/mL. Over a 5-month period (spring/summer of 2023), 8 healthy neonatal foals were administered each protocol at least 48 hours apart. Synovial fluid was obtained 30 minutes after IVRLP. The systemic amikacin dose was administered at the time of tourniquet release (30 minutes), and plasma samples were obtained over a 24-hour period. The observed synovial fluid and plasma amikacin concentrations were not different between protocols, so a single least square means estimate was predicted for each sample type, at each time point. The amikacin concentration estimate in synovial fluid was 238.5 μg/mL (95% CI, 146.1 to 330.9) 30 minutes after IVRLP and in plasma was 66.3 μg/mL (95% CI, 57.5 to 75.1) 30 minutes after administration of the systemic dose. Some foals did not reach the synovial fluid therapeutic target in all joints studied. These results support our hypotheses and suggest that administering amikacin systemically and via IVRLP as described can achieve therapeutic plasma and synovial fluid concentrations in neonatal foals. Concurrent systemic and IVRLP administration of amikacin as described can be clinically effective in the treatment of sepsis with concurrent septic arthritis in neonatal foals.

Amikacin (AMK) is among the narrow therapeutic index drugs that are still being used in neonates for early-onset and late-onset sepsis. The pharmacokinetic and pharmacodynamic properties of drugs in neonates vary across ages, especially in premature babies. Neonates exhibit differences in body composition and organ function, which can influence drug disposition and response. Although much literature has discussed the pharmacokinetics of AMK in neonates, this review aims to explore the pharmacokinetic properties of AMK in Asian neonates and infants. Seven articles were included in this review, with evaluation conducted on Malaysian, Japanese, Pakistani, Indian, Korean, and Thai neonates. Overall, 702 neonates were included in these studies, consisting of both preterm and term neonates, with one study focusing exclusively on low-birth-weight neonates. This review highlights that a high dose of AMK with once-daily dosing shows a better option for achieving therapeutic concentrations. Nevertheless, variability in pharmacokinetic profiles across neonatal age was observed. Factors affecting these pharmacokinetic changes need to be addressed during the initiation of AMK therapy in neonates to ensure optimal outcomes.

Amikacin (AMK) is used to treat gram-negative bacterial infections in intensive care unit (ICU) patients. However, its narrow therapeutic range and high interindividual variability can lead to toxicity and ineffectiveness. This study aimed to establish a roadmap for AMK therapeutic drug monitoring in critically ill patients with cancer to provide a Bayesian estimator of bedside applicability. An observational retrospective study was conducted on oncological patients admitted to the ICU, treated with AMK as a 30-min intravenous infusion at 5.8-39.2 mg/kg. The plasma concentrations were analyzed using a nonlinear mixed-effects modeling approach. Covariate analyses were performed using anthropometric and laboratory data, concomitant drugs, and comorbidities. The model predictive performance was compared with previous AMK dosing approaches using the Bland-Altman method. The concentration-time profiles were best described using a one-compartment model with linear elimination. The estimated glomerular filtration rate was a significant covariate of clearance (CL), explaining 16% of the interpatient variability. Body weight was positively correlated with the volume of distribution, accounting for 4% of the variability. Our model reduced the bias in the estimates of individual CL values compared with that of other available methods and was further implemented in DoseMeRx for real-time application at the bedside. This study provides an effective example of a Bayesian estimation method for individualizing AMK doses in critically ill patients with cancer. Collecting more comprehensive patient information, including additional biomarkers for renal function, could further refine the model and improve its predictive performance in this special population.

BackgroundAcute kidney injury (AKI) requiring renal replacement therapy (RRT) is common in intensive care units (ICUs), yet optimal amikacin dosing in this context remains poorly understood.MethodsWe conducted a prospective observational study across 18 French hospitals from April 2020 to January 2022. Adult ICU patients (aged > 18 years) receiving their first amikacin dose while on RRT were included. Data on demographics, RRT modalities, amikacin dosing, and therapeutic drug monitoring were collected. Using a pharmacokinetic modeling approach, we evaluated various amikacin regimens and simulated target attainment probabilities across different minimum inhibitory concentrations (MICs).ResultsA total of 111 patients were included, with approximately two-thirds receiving continuous RRT. The median amikacin dose was 27 (25–30) mg/kg. Amikacin peak (Cmax) and trough concentrations were monitored in 53 (47.8%) and 76 (68.5%) patients, respectively. Continuous RRT and a history of chronic kidney disease reduced dialytic clearance. For a MIC ≤ 4 mg/L, a 15 mg/kg amikacin dose achieved Cmax/MIC and AUC/MIC targets in ≥ 90% of patients on intermittent dialysis, while 20 mg/kg was required for those on continuous dialysis. For a MIC = 8 mg/L, a 30 mg/kg dose was necessary to achieve Cmax/MIC ≥ 8.ConclusionsOur findings highlight suboptimal adherence to amikacin monitoring guidelines in ICU patients on RRT. Using pharmacokinetic modeling, we identified amikacin dosing recommendations ranging from 15 to 35 mg/kg to optimize efficacy and minimize risks, depending on MIC and dialysis modality.

Amikacin is frequently used for the treatment of neonatal sepsis. The Dutch Pediatric Formulary recommends a complex pharmacokinetic (PK) model-derived dosing regimen, which consists of dosing categories based on postnatal age and weight that results in adequate PK/pharmacodynamic (PK/PD) target attainment. However, a simplified dosing regimen may be easier to apply in clinical practice. We evaluated PK/PD target attainment of amikacin in neonates using this simplified or complex dosing regimen. This retrospective cohort study included neonates with routinely measured amikacin concentrations at the neonatal intensive care units of the Amsterdam University Medical Center (simplified dosing regimen) or University Hospitals Leuven (complex dosing regimen). Peak (Cmax) and trough (Cmin) concentrations and the area under the concentration-time curve (AUC) for the first dosing interval were calculated by Bayesian estimation for both populations. Targets of Cmax (≥15, ≥25, and ≥35 mg/L), Cmin (≤3 and ≤5 mg/L), and AUC/minimal inhibitory concentration (MIC: 2, 4, and 8 mg/L for Enterobacterales species) for bacteriostasis and 1-log reduction were evaluated. A target attainment of ≥90% was considered adequate. In total, 366 neonates (768 concentrations) and 579 neonates (1,195 concentrations) received the simplified and complex dosing regimen, respectively. Both regimens achieved target attainment of 100% for Cmax ≥ 15 mg/L, Cmin ≤ 5 mg/L, AUC/MIC for bacteriostasis, and AUC/MIC for 1-log reduction up to a MIC of 2 mg/L. Target attainment was achieved for less stringent targets (Cmax ≥ 15 mg/L, Cmin ≤ 5 mg/L, and AUC/MIC for bacteriostasis) with the simplified and complex amikacin dosing regimen. Clinicians can choose one of both dosing regimens, depending on their local circumstances, and the availability of integrated (electronic) prescription tools.

Background/Objectives: Guidelines recommend adjusting amikacin dosing based on patients' renal function. Nevertheless, for critically ill cancer patients, the renal function equations based on serum creatinine levels have low or no correlation with amikacin clearance. Considering this, using real-world data, we built an amikacin PBPK model to predict amikacin plasma concentrations in critically ill oncologic patients stratified by renal impairment levels. Further, the model was applied for dose stratification and individualization (digital twin strategy) in this population. Methods: In the Therapeutic Drug Monitoring (TDM) study, 368 amikacin pharmacokinetic analyses from 184 critically ill cancer patients were enrolled in three cohorts. A full-body PBPK model was developed using PK-Sim v. 11.3. Results: The final PBPK model accounted for two groups of critically ill cancer patients with mild (creatinine clearance; CLcr ≥ 60 mL/min) or severe (CLcr < 60 mL/min) renal dysfunction. In the dose stratification strategy, at the 7th dose, cancer patients with CLcr ≥ 60 mL/min under regimens 20 mg/kg (q24h); 25 mg/kg (q24h); 25 mg/kg (q48h); and 30 mg/kg (q72h) have probability of ≥69% of the patients achieving the efficacy target (AUC/MIC > 80, MIC of 4 mg/L), while cancer patients with CLcr < 60 mL/min under regimens 7.5 mg/kg (q24h); 15 mg/kg (q24h); 15 mg/kg (q48h); and 20 mg/kg (q36h) have ≥90% probability of achieving the same efficacy target. Conclusions: Our MIPD approach demonstrates potential in optimizing amikacin dosing for critically ill cancer patients. However, it does not eliminate the need for TDM due to unexplained variability still not accounted for by the PBPK model.

BackgroundGentamicin (GM) is frequently prescribed in the neonatal population, and its pharmacokinetics (PK) in this population are therefore well-studied. However, recent findings of diminished GM efficacy against Pseudomonas spp. have prompted increased use of other aminoglycosides with less well-defined PK, which poses a challenge for model-informed precision dosing (MIPD). Although ultimately the goal for dose individualization will be drug-specific models for neonatal patients, as an interim measure, this study investigates the performance of GM models in neonates receiving amikacin (AK) and tobramycin (TO).Patient Characteristics. Numbers are represented as counts or median (range) as appropriate. GA: gestational age; PMA: post-menstrual age; WT: weight; CR: creatinine.MethodsNeonatal patient data entered into the InsightRX Nova model-informed precision dosing (MIPD) platform during routine clinical care were de-identified and analyzed retrospectively. Patients were included if their postnatal age was < 90 days or their postmenstrual age was < 44 weeks, received at least one dose of AK or TO and provided at least one therapeutic drug monitoring sample (TDM) within 48 hours of an administered dose. For each patient and for each model, samples were grouped by dosing interval and iteratively used to predict future levels using Bayesian forecasting, mimicking clinical implementation of MIPD. Prediction error was assessed using root mean square error (RMSE), mean percent error (MPE), and Accuracy, defined as percent of samples within 20% of predicted values or correctly identifying a trough under 1 mg/L.RMSE for aminoglycoside models developed on amikacin, gentamicin or tobramycin data sets and evaluated on clinical amikacin and tobramycin data sets. The best native performing model for each clinical data set serves as the reference model & is listed first, with subsequent models ordered by best to worst performance. Asterisks denotes statistical significance relative to the reference model.ResultsOverall, 14 AK courses with 31 AK TDMs, and 48 TO courses with 63 TO TDMs were included in the analysis (Table 1). RMSE, MPE, and Accuracy are displayed in Figures 1-3. Data on TO peaks were excluded due to low sample size. Of the AK courses, most GM models outperformed available AK models for both peak and trough levels. Of the TO courses, GM models exhibited significantly improved RMSE and MPE values, as well as significantly higher rates of accuracy when predicting trough levels compared to those of the available TO model.Mean percent error for aminoglycoside models developed on amikacin, gentamicin or tobramycin data sets and evaluated on clinical amikacin and tobramycin data sets. The best native performing model for each clinical data set serves as the reference model & is listed first, with subsequent models ordered by best to worst performance. Asterisks denotes statistical significance relative to the reference model.ConclusionPK models developed in neonates receiving GM match or outperform drug-specific models in predicting AK and TO exposures in neonates. Further research is needed to better understand model performance for TO peak levels in neonates and clinical implications of cross-module model use.Accuracy for aminoglycoside models developed on amikacin, gentamicin or tobramycin data sets and evaluated on clinical amikacin and tobramycin data sets. The best native performing model for each clinical data set serves as the reference model & is listed first, with subsequent models ordered by best to worst performance. Asterisks denotes statistical significance relative to the reference model.DisclosuresTiffany Lee, PharmD, InsightRX: Employee|InsightRX: Stocks/Bonds (Private Company) Jasmine Hughes, PhD, InsightRX: Employee|InsightRX: Stocks/Bonds (Private Company) Jon Faldasz, PharmD, BCPS, InsightRX: Employee|InsightRX: Stocks/Bonds (Private Company)

Amikacin is sequestered in polyacrylonitrile filters. Methods mitigating sequestration are unknown. Amikacin elimination in a polyacrylonitrile-derived filter preloaded with amikacin was studied in a preliminary study. Amikacin concentrations were determined using an immunochemical method. Prismaflex™, Baxter-Gambro, and the ST™150 filter were used. Sessions were performed in a continuous diafiltration mode. Diafiltration flow rate was set to 2500 mL/h and filtration to 500 mL/h pre- and 1000 mL/h post-dilution. Net loss was set to zero. In sessions with preload, a 150 mg dose of amikacin was injected in the first 1 L bag of physiological saline when starting the priming. NeckEpur® method was used for pharmacokinetic calculations. In the central compartment (CC), the mean initial concentration in the sessions without and with preload was 81.8 ± 6.0 mg/L. There were no significant differences in the AUCcc and AUCinlet without or with preload. The preloading dose induced a significant increase in the AUCoutlet. Compared with sessions without preload, the clearance from the CC in sessions with preload decreased from 4.94 ± 0.43 to 3.75 ± 0.32 L/h, respectively. The elimination rates by diafiltration and sequestration in the sessions without and with preload were 82.3 ± 6.2/17.8 ± 6.2% and 125 ± 9.2%/0 ± 0%, respectively. The 150 mg loading dose was eliminated by diafiltration (42.5%) and by sequestration (57.5%). Preloading filter with amikacin modifies the disposition of amikacin by preventing further sequestration. Studies are needed to define an efficient preloading dosage regimen in actual condition of use.

BackgroundMaintaining amikacin concentrations within a specific therapeutic window is crucial to avoid sub-therapeutic or toxic levels. This study aimed to design a dosing nomogram for amikacin in neonates using a Population Pharmacokinetic (PopPK) modeling approach.MethodsPopPK model was developed using 101 amikacin concentrations from 80 neonates and validated using model diagnostics, and empirical Bayesian forecasting was performed. Pharmacokinetic profiles were simulated for virtual subjects with a range of covariates to identify suitable dosage regimens. Dosage regimens with the highest probability for the target group were selected to design the dosing nomogram.ResultsA two-compartment PK model best described the study data. Body weight (WT), serum creatinine (SCR), and post-natal age (PNA) affected the clearance of amikacin. The model predictions are with less than 15% absolute prediction error. WT and SCR were divided into five groups each, with each group repeated for every week of PNA for four weeks for dosing nomogram development.ConclusionA PopPK model was developed and successfully-predicted concentrations in the study population. This model was used to develop a nomogram considering significant covariates like WT, SCR, and PNA. The proposed dosing nomogram can assist clinicians in developing individualized dosage regimens.ImpactPopulation pharmacokinetic (PopPK) models for amikacin in term neonates were developed using clinical data from an Indian clinical setting and successfully-predicted the amikacin concentrations for the study population.Pharmacokinetic simulations with virtual subjects were used to calculate the probability of target attainment for different dosing regimens.The proposed dosing nomogram can potentially assist clinicians in designing optimal amikacin dosage regimens for neonates.

To report the clinical use, adverse events, and outcomes after using amikacin in 30% poloxamer 407 (amikacin-P407) during open wound management or in a closed wound application in dogs. 29 client-owned dogs. Medical records from January 2017 to August 2023 from a single hospital were reviewed for dogs that received amikacin-P407 in an open or closed wound application. Information reviewed included signalment, nature of wound and/or surgical site infection (SSI), bacterial cultures, amikacin dose, gel volume, route of administration, estimated wound surface area, biochemistry parameters, urine casts, wound progression, and general clinical outcome. Amikacin-P407 was applied during open wound care (10 dogs), via injection (5 dogs), and at time of wound closure (13 dogs) and was used both in open and closed wound management (1 dog). Wounds were associated with SSIs in 18 of 30 sites. Multidrug resistance was noted in 21 of 30 preapplication cultures. Median amikacin dose was 14.5 mg/kg (range, 3 to 59.5 mg/kg), median total volume was 5.0 mL (range, 1 to 12 mL), and median tissue surface area was 6.6 cm2 (range, 1.6 to 36 cm2), for a local wound dose of 62.5 mg/cm2 (range, 6.9 to 214.3 mg/cm2). No short-term adverse local or systemic effects were noted in any wounds or dogs. No dehiscence was seen in 17 of 19 closed sites. The results of this case series suggested that Amikacin-P407 can be applied in a variety of ways with no adverse effects. Amikacin-P407 may be considered in open wound management or in a closed setting for infected wounds and SSIs.

To establish pilot data on the plasma concentrations of SC amikacin at 2 doses in red-eared sliders and evaluate concurrent plasma biochemistry parameters. 8 adult red-eared sliders (Trachemys scripta elegans). Amikacin was administered SC at target doses of 5 and 10 mg/kg with a 3-week washout period. Blood samples were collected at 0, 24, 48, 72, and 96 hours postadministration. Plasma amikacin concentrations were quantified using liquid chromatography tandem mass spectrometry. Plasma biochemistry analyses were performed before amikacin administration, 1 week post 5-mg/kg administration, and 1 week post 10-mg/kg administration. Mean maximum amikacin plasma concentrations were recorded 24 hours after 5-mg/kg and 10-mg/kg dosing and were 17.5 ± 2.32 µg/mL and 23.6 ± 2.92 µg/mL, respectively. Mean plasma concentrations after 5-mg/kg dosing steadily decreased to 9.1 ± 0.92 µg/mL by 96 hours postadministration. Amikacin remained detectable in all plasma samples 3 weeks post 5-mg/kg dosing with a mean plasma concentration of 1.04 ± 0.22 µg/mL. Mean plasma concentrations after 10-mg/kg dosing did not decrease over the 96-hour study period. There were no clinically relevant changes in biochemistry parameters. Amikacin persists at detectable plasma levels for at least 3 weeks after SC administration of a 5-mg/kg dose in red-eared sliders, which has not previously been reported in any species. No biochemistry changes consistent with renal toxicity occurred after either dose. Use caution with repeated amikacin dosing in this species until further studies can better characterize cumulative amikacin pharmacokinetics and toxic threshold.

Purpose: This study aimed to externally validate the population pharmacokinetic (popPK) model of amikacin and assess the applicability of Bayesian forecasting approach in individualizing amikacin dosing for critically ill patients. Materials and Methods: Retrospective data from 121 ICU patients with 231 blood amikacin concentrations were used to evaluate the predictive performance of the model published by A.H. Nguyen which was developed previously from patients in the same department. The model was evaluated based on a priori and a posteriori approach using relative bias (rBias), relative root mean squared error (rRMSE), and Visual Predictive Checks. For Bayesian forecasting, the study investigated the ability to predict peak concentrations by using solely a middle level in dosing interval. The rBias and rRMSE and the clinical agreement evaluation based on a threshold of 45 mg/L was applied for this purpose. The forecast performance between Bayesian estimation and first-order pharmacokinetic calculation was compared based on trough concentrations, with Bias and RMSE indices. Results: The A.H. Nguyen model was appropriate for both a priori and a posteriori prediction, with rBias values of 18.40% and 2.42%, respectively. The Bayesian forecasting method demonstrated good predictive performance when comparing forecasted peak concentrations to observations, with rBias of 6.81% and rRMSE of approximately 30%. An excellent agreement (over 85%) between observed- and forecast-peak concentrations was achieved. No difference was found in forecasting trough concentration by Bayesian estimation using one-level or two-level. However, the trough level estimated by the Bayesian methods resulted in a positive bias of 1.25 mg/L in comparison with first-order PK calculation. Conclusions: The A.H. Nguyen model could be applicable in a model-based TDM for Vietnamese ICU patients. Bayesian forecasting using only middle concentration might be sufficient for the dose individualization of amikacin for both efficacy and safety monitoring.

Pharmacokinetics employs complex mathematics to study, model, and predict how drugs are absorbed, distributed, metabolized, and excreted by the body. Amikacin, as a model drug with a narrow therapeutic window, requires Therapeutic Drug Monitoring (TDM) to ensure safety. This study developed an Android-based pharmacokinetic calculator, the "Indonesia Pharmacokinetic Calculator" (KFI), to assist clinical practitioners in quickly and accurately calculating pharmacokinetic parameters using patient weight and Amikacin doses as inputs. The application is designed to provide calculations of pharmacokinetic parameters, a pharmacokinetic simulation graph (plasma concentration-time curve), and predictions of individual patient amikacin plasma concentrations to assess therapeutic effectiveness and minimize toxicity risks. The rigorous testing process has demonstrated that KFI reliably produces expected output data, enhancing clinical pharmacy services in Indonesia through the integration of cutting-edge technology. This tool is expected to improve therapeutic outcomes, particularly for sepsis patients, by facilitating accurate and efficient pharmacokinetic calculations.

Objectives: The primary purpose of this research was to evaluate the loading dose and maintenance dose of amikacin in the treatment of sepsis from intensive care unit (ICU) patients from May to July 2023 at the dr. Ramelan Naval Central Hospital in Indonesia. The analysis focus on the use of therapeutic drug monitoring (TDM) results to improve efficacy and safety of amikacin therapy. Material and Methods: A total of 8 sepsis patients received amikacin for 5 days. The loading dose was administered regardless of the renal function and was calculated of 7.5mg / kg body weight, administered intravenously as a bolus. The subsequent maintenance dose was delivered 4 hours following the loading dose at 15mg / kg body weight by an intermittent drip for 1 hour. The TDM measurement was conducted twice on the third day, with sampling conducted at 1.5 and 4 hours following the administration of the third amikacin maintenance dose. Results: The TDM results revealed that the amikacin t½ elpatients demonstrated Cpmax/MIC indices exceeding 8, while three patients exhibited AUC0-24h/MIC indices surpassing 75. The data showed variabilities in pharmacokinetic characteristics of amikacin in the sepsis patients due to comorbidities specifically patient’s creatinine clearance. Conlusion: The dose administered at efficacious doses attaining the desired PK/PD target while minimizing the risk of toxicity The findings of pharmacokinetic parameters on septis patient in Indonesia give valuable insights into the potential of amikacin therapy to enhance the possibility of achieving an effective treatment.

IntroductionAn effective rifampicin-resistant tuberculosis (RR-TB) treatment regimen should include prevention of resistance amplification. While bedaquiline (BDQ) has been recommended in all-oral RR-TB treatment regimen since 2019, resistance is rising at...